Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants

ABSTRACT

This invention is directed to poly-hydroxylated monocyclic N-heterocyclic derivatives selected from the following formulae:  
                 
 
     wherein Z 1 , Z 2 , R 1 , R, R 3 , R 4 , R 5 , R 6 , and R 7  are defined herein. These compounds are useful as anti-coagulants.

FIELD OF THE INVENTION

[0001] The present invention is directed to polyhydroxylated monocyclicN-heterocyclic derivatives and their pharmaceutically acceptable salts,which inhibit the enzyme, factor Xa, thereby being useful asanti-coagulants. It also relates to pharmaceutical compositionscontaining the derivatives or their pharmaceutically acceptable salts,and methods of their use.

BACKGROUND OF THE INVENTION

[0002] Factor Xa is a member of the trypsin-like serine protease classof enzymes. A one-to-one binding of factors Xa and Va with calcium ionsand phospholipid forms the prothrombinase complex which convertsprothrombin to thrombin. Thrombin, in turn, converts fibrinogen tofibrin which polymerizes to form insoluble fibrin.

[0003] In the coagulation cascade, the prothrombinase complex is theconvergent point of the intrinsic (surface activated) and extrinsic(vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p.10363; and Cell (1988), Vol. 53, pp. 505-518). The model of thecoagulation cascade has been refined further with the discovery of themode of action of tissue factor pathway inhibitor (TFPI) (Seminars inHematology (1992), Vol. 29, pp. 159-161). TFPI is a circulatingmulti-domain serine protease inhibitor with three Kunitz-type domainswhich competes with factor Va for free factor Xa. Once formed, thebinary complex of factor Xa and TFPI becomes a potent inhibitor of thefactor VIIa and tissue factor complex.

[0004] Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the “Xa burst” pathway and by the factorIXa-VIIIa complex (TENase) of the “sustained Xa” pathway in thecoagulation cascade. After vessel injury, the “Xa burst” pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the “sustained Xa”pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the “Xa burst”pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

[0005] The primary advantage of inhibiting factor Xa over thrombin inorder to prevent coagulation is the focal role of factor Xa versus themultiple functions of thrombin. Thrombin not only catalyzes theconversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V toVa, and factor XI to XIa, but also activates platelets, is a monocytechemotactic factor, and mitogen for lymphocytes and smooth muscle cells.Thrombin activates protein C, the in vivo anti-coagulant inactivator offactors Va and VIIIa, when bound to thrombomodulin. In circulation,thrombin is rapidly inactivated by antithrombin III (ATIII) and heparincofactor II (HCII) in a reaction which is catalyzed by heparin or otherproteoglycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique “tethered ligand”thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

[0006] Published data with the proteins antistasin and tickanti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors areefficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67,pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).

[0007] The active site of factor Xa can be blocked by either amechanism-based or a tight binding inhibitor (a tight binding inhibitordiffers from a mechanism-based inhibitor by the lack of a covalent linkbetween the enzyme and the inhibitor). Two types of mechanism-basedinhibitors are known, reversible and irreversible, which aredistinguished by ease of hydrolysis of the enzyme-inhibitor link(Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci.(1987), Vol. 8, pp. 303-307). A series of guanidino compounds areexamples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19,pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acidderivatives have also been shown to be tight-binding inhibitors ofthrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series ofarylamidine-containing compounds, including 3-amidinophenylarylderivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) andbis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp.545-548). However, these compounds demonstrate poor selectivity forfactor Xa.

RELATED DISCLOSURES

[0008] European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives. These derivatives are stated tobe capable of showing a strong anticoagulant effect through reversibleinhibition of factor Xa.

[0009] The synthesis of α,α′-bis(amidinobenzylidene)cycloalkanones andα,α′-bis(amidinobenzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

[0010] U.S. Pat. No. 5,451,700 (Morrissey et al.) describes amidinocompounds. These compounds are stated to be useful as selective LTB₄receptor antagonists.

[0011] U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl)cyclic urea derivatives. These compounds are stated to be factor Xainhibitors, thereby being useful as anticoagulants.

[0012] U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E)and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. Thesecompounds are disclosed as being factor Xa inhibitors, thereby beinguseful as anticoagulants.

[0013] PCT Published Patent Application WO/96/28427 (Buckman et al.)describes benzamidine derivatives. These compounds are stated to befactor Xa inhibitors, thereby being useful as anticoagulants.

[0014] PCT Published Patent Application WO/97/21437 (Arnaiz et al.)describes naphthyl substituted benzimidazole derivatives. Thesecompounds are disclosed as being factor Xa inhibitors, thereby beinguseful as anticoagulants.

[0015] PCT Published Patent Application WO/97/29067 (Kochanny et al.)describes benzamidine derivatives that are substituted by amino acid andhydroxy acid derivatives. These compounds are stated to be factor Xainhibitors, thereby being useful as anticoagulants.

[0016] The above references, published patent applications and U.S.patents are herein incorporated in full by reference.

SUMMARY OF THE INVENTION

[0017] This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity.

[0018] Accordingly, in one aspect, this invention provides compoundsselected from the group consisting of the following formulae:

[0019] wherein:

[0020] A is —C(R⁸)═ or —N═ (where R⁸ is hydrogen, alkyl or halo);

[0021] Z¹ is —O—, —N(R⁹)—, —CH₂O— or —S(O)_(n)— (where n is 0 to 2);

[0022] Z² is —O—, —N(R⁹)—, —OCH₂— or —S(O)_(n)— (where n is 0 to 2);

[0023] R¹ and R⁴ are each independently hydrogen, halo, alkyl, nitro,—OR⁹, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or—N(H)S(O)₂R¹¹;

[0024] R² is —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹¹,—C(NH)N(H)C(O)R⁹, —C(NH)N(H)S(O)₂R¹¹, or —C(NH)N(H)C(O)N(H)R⁹;

[0025] R³ is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino,—OR⁹, —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹²—C(O)N(R⁹)R¹⁰,—CH(OH)C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —R¹²—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹²—C(O)OR⁹,—N(R⁹)C(O)R⁹, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

[0026] R⁵ and R⁶ are independently hydrogen, halo, alkyl, haloalkyl,nitro, —N(R⁹)R¹⁰, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰,—N(R⁹)C(O)N(R⁹)R¹⁰, —N(R⁹)C(O)R¹⁰, —N(R⁹)S(O)₂R¹¹, or—N(R⁹)C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰;

[0027] R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ or—X—C([C(R¹³)H]_(p)—C(R¹³)H₂)₂H where:

[0028] p is 0 to 5;

[0029] X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—;

[0030] and each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)R¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰,or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2);

[0031] or R⁷ is selected from the group consisting of the followingformulae:

[0032] where

[0033] q is 0 to 4;

[0034] p is 0 to 5;

[0035] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—(CH₂)_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—NOR⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0036] each R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where:

[0037] each r is independently 0 to 5, and

[0038] each X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; and

[0039] each R¹³ is independently —[C(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2);

[0040] each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl);

[0041] each R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); and

[0042] each R¹² is independently an alkylene or alkylidene chain;

[0043] as a single stereoisomer or a mixture thereof; or apharmaceutically acceptable salt thereof.

[0044] In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

[0045] In another aspect, this invention provides a method of treating ahuman having a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

[0046] In another aspect, this invention provides a method of treating ahuman having a disease-state alleviated by the inhibition of factor Xa,which method comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

[0047] In another aspect, this invention provides a method of inhibitinghuman factor Xa in vitro by the administration of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0048] Definitions

[0049] As used in the specification and appended claims, unlessspecified to the contrary, the following terms have the meaningindicated:

[0050] “Alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to six carbon atoms, and which is attachedto the rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

[0051] “Alkoxy” refers to a radical of the formula —OR_(a) where R_(a)is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy,1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy(t-butoxy), and the like.

[0052] “Alkoxycarbonyl” refers to a radical of the formula —C(O)OR_(a)where R_(a) is alkyl as defined above, e.g., methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl(iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxycarbonyl,1,1-dimethylethoxycarbonyl (t-butoxycarbonyl), and the like.

[0053] “Alkylene chain” refers to straight or branched chain divalentradical consisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to six carbon atoms, e.g., methylene,ethylene, propylene, n-butylene and the like.

[0054] “Alkylidene chain” refers to a straight or branched chainunsaturated divalent radical consisting solely of carbon and hydrogenatoms, having from one to six carbon atoms, wherein the unsatuation ispresent only as double bonds and wherein a double bond can exist betweenthe first carbon of the chain and the rest of the molecule, e.g.,ethylidene, propylidene, n-butylidene, and the like.

[0055] “Aryl” refers to a phenyl or naphthyl radical.

[0056] “Aralkyl” refers to a radical of the formula —R_(a)R_(b) whereR_(a) is an alkyl radical, as defined above, substituted by R_(b), anaryl radical, as defined above, e.g., benzyl.

[0057] “Aralkoxy” refers to a radical of the formula —OR_(c) where R_(c)is an aralkyl radical as defined above, e.g., benzyloxy, and the like.

[0058] “Amidino” refers to the radical —C(NH)NH₂.

[0059] “Aminocarbonyl” refers to the radical —C(O)NH₂.

[0060] “Dialkylamino” refers to a radical of the formula —N(R_(a))R_(a)where each R_(a) is independently an alkyl radical as defined above,e.g., dimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.

[0061] “Dialkylaminocarbonyl” refers to a radical of the formula—C(O)N(R_(a))R_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl,diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl,and the like.

[0062] “Halo” refers to bromo, chloro, iodo or fluoro.

[0063] “Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

[0064] “(1,2)-Imidazolyl” refers to an imidazolyl radical attached ateither the 1- or 2-position.

[0065] “(1,2)-Imidazolinyl” refers to a 4,5-dihydroimidazolyl radicalattached at either the 1- or the 2-position.

[0066] “Monoalkylamino” refers to a radical of the formula —NHR_(a)where R_(a) is an alkyl radical as defined above, e.g., methylamino,ethylamino, propylamino, and the like.

[0067] “Monoalkylaminocarbonyl” refers to a radical of the formula—C(O)NHR_(a) where R_(a) is an alkyl radical as defined above, e.g.,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and thelike.

[0068] “(1,2)-Tetrahydropyrimidinyl” refers to a tetrahydropyrimidinylradical attached at either the 1- or 2-position.

[0069] “Optional” or “optionally” means that the subsequently describedevent of circumstances may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not. For example, “optionally substituted aryl” meansthat the aryl radical may or may not be substituted and that thedescription includes both substituted aryl radicals and aryl radicalshaving no substitution.

[0070] “Pharmaceutically acceptable salt” includes both add and baseaddition salts.

[0071] “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases, which are not biologically or otherwise undesirable, andwhich are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, and organic acids such as acetic acid, trifluoroacetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike.

[0072] “Pharmaceutically acceptable base addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree acids, which are not biologically or otherwise undesirable. Thesesalts are prepared from addition of an inorganic base or an organic baseto the free acid. Salts derived from inorganic bases include, but arenot limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

[0073] “Therapeutically effective amount” refers to that amount of acompound of the invention which, when administered to a human in needthereof, is sufficient to effect treatment, as defined below, fordisease-states characterized by thrombotic activity. The amount of acompound of the invention which constitutes a “therapeutically effectiveamount” will vary depending on the compound, the disease-state and itsseverity, and the age of the human to be treated, but can be determinedroutinely by one of ordinary skill in the art having regard to his ownknowledge and to this disclosure.

[0074] “Treating” or “treatment” as used herein covers the treatment ofa disease-state in a human, which disease-state is characterized bythrombotic activity, and includes:

[0075] (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

[0076] (ii) inhibiting the disease-state, i.e., arresting itsdevelopment; or

[0077] (iii) relieving the disease-state, i.e., causing regression ofthe disease-state.

[0078] The yield of each of the reactions described herein is expressedas a percentage of the theoretical yield.

[0079] The compounds of the invention, or their pharmaceuticallyacceptable salts, may have asymmetric carbon atoms, oxidized sulfuratoms or quaternized nitrogen atoms in their structure. The compounds ofthe invention and their pharmaceutically acceptable salts may thereforeexist as single stereoisomers, racemates, and as mixtures of enantiomersand diastereomers. The compounds may also exist as geometric isomers.All such single stereoisomers, racemates and mixtures thereof, andgeometric isomers are intended to be within the scope of this invention.

[0080] The nomenclature used herein is a modified form of the I.U.P.A.C.system wherein the compounds of the invention are named aspolyhydroxylated derivatives of benzamidine. For example, a compound ofthe invention selected from formula (I):

[0081] wherein A is —N═, Z¹ and Z² are both —O—; R¹ and R⁴ are bothhydrogen, R² is —C(NH)NH₂, R³ is —C(O)N(R⁹)R¹⁰ (where R⁹ and R¹⁰ areboth methyl), R⁵ and R⁶ are both fluoro, R⁷ is selected from theformula:

[0082] where R¹⁴— is in the 2-position of the tetrahydrofuranyl moietyand is —X—(CH₂)_(p)— where X is —O— and p is 1; and q is three and oneR¹³ is in the 3-position of the tetrahydrofuranyl moiety and isdimethylamino and another R¹³ is in the 4-position of thetetrahydrofuranyl moiety and is hydroxy, and another R¹³ is in the5-position of the tetrahydrofuranyl moiety and is —CH₂—OH; i.e., thecompound of the following formula:

[0083] is named herein as3-[[3,5-difluoro-6-[3-(dimethylaminocarbonyl)phenoxy]-4-[[3-dimethylamino-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]methoxy]pyridin-2-yl]oxy]benzamidine.

[0084] For purposes of this invention, parenthesis are used to denotesubstituents of a main atom and brackets are used to denote repeatingsections of the substituent. For example, —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂where p is 2 refers to the substituent of the formula:

[0085] Utility and Administration

[0086] A. Utility

[0087] The compounds of the invention are inhibitors of the serineprotease, factor Xa, and are therefore useful in disease-statescharacterized by thrombotic activity based on factor Xa's role in thecoagulation cascade (see Background of the Invention above). A primaryindication for the compounds is prophylaxis for long term risk followingmyocardial infarction. Additional indications are prophylaxis of deepvein thrombosis (DVT) following orthopedic surgery or prophylaxis ofselected patients following a transient ischemic attack. The compoundsof the invention may also be useful for indications in which coumarin iscurrently used, such as for DVT or other types of surgical interventionsuch as coronary artery bypass graft and percutaneous transluminalcoronary angioplasty. The compounds are also useful for the treatment ofthrombotic complications associated with acute promyelocytic leukemia,diabetes, multiple myelomas, disseminated intravascular coagulationassociated with septic shock, purpura fulminanas associated infection,adult respiratory distress syndrome, unstable angina, and thromboticcomplications associated with aortic valve or vascular prosthesis. Thecompounds are also useful for prophylaxis for thrombotic diseases, inparticular in patients who have a high risk of developing such disease.

[0088] In addition, the compounds of the invention are useful as invitro and in vivo diagnostic reagents for selectively inhibiting factorXa without inhibiting other components of the coagulation cascade.

[0089] B. Testing

[0090] The primary bioassays used to demonstrate the inhibitory effectof the compounds of the invention on factor Xa are simple chromogenicassays involving only serine protease, the compound of the invention tobe tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for tPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319).

[0091] Another bioassay useful in demonstrating the utility of thecompounds of the invention in inhibiting factor Xa demonstrates thepotency of the compounds against free factor Xa in citrated plasma. Forexample, the anticoagulant efficacy of the compounds of the inventionwill be tested using either the prothrombin time (PT), or activatedpartial thromboplastin time (aPTT) while selectivity of the compounds ischecked with the thrombin clotting time (TCT) assay. Correlation of theK_(i) in the primary enzyme assay with the K_(i) for free factor Xa incitrated plasma will screen against compounds which interact with or areinactivated by other plasma components. Correlation of the K_(i) withthe extension of the PT is a necessary in vitro demonstration thatpotency in the free factor Xa inhibition assay translates into potencyin a clinical coagulation assay. In addition, extension of the PT incitrated plasma can be used to measure duration of action in subsequentpharmacodynamic studies.

[0092] For further information on assays to demonstrate the activity ofthe compounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

[0093] C. General Administration

[0094] Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

[0095] Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

[0096] The preferred route of administration is oral, using a convenientdaily dosage regimen which can be adjusted according to the degree ofseverity of the disease-state to be treated. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention, or a pharmaceutically acceptable saltthereof, is formed by the incorporation of any of the normally employedexcipients, such as, for example, pharmaceutical grades of mannitol,lactose, starch, pregelatinized starch, magnesium stearate, sodiumsaccharine, talcum, cellulose ether derivatives, glucose, gelatin,sucrose, citrate, propyl gallate, and the like. Such compositions takethe form of solutions, suspensions, tablets, pills, capsules, powders,sustained release formulations and the like.

[0097] Preferably such compositions will take the form of capsule,caplet or tablet and therefore will also contain a diluent such aslactose, sucrose, dicalcium phosphate, and the like; a disintegrant suchas croscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

[0098] The compounds of the invention, or their pharmaceuticallyacceptable salts, may also be formulated into a suppository using, forexample, about 0.5% to about 50% active ingredient disposed in a carrierthat slowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

[0099] Liquid pharmaceutically administrable compositions can, forexample, be prepared by dissolving, dispersing, etc., a compound(s) ofthe invention (about 0.5% to about 20%), or a pharmaceuticallyacceptable salt thereof, and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, ethanol and the like, to thereby form a solution orsuspension.

[0100] If desired, a pharmaceutical composition of the invention mayalso contain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

[0101] Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

[0102] The compounds of the invention, or their pharmaceuticallyacceptable salts, are administered in a therapeutically effective amountwhich will vary depending upon a variety of factors including theactivity of the specific compound employed; the metabolic stability andlength of action of the compound; the age, body weight, general health,sex, and diet of the patient; the mode and time of administration; therate of excretion; the drug combination; the severity of the particulardisease-states; and the host undergoing therapy. Generally, atherapeutically effective daily dose is from about 0.14 mg to about 14.3mg/kg of body weight per day of a compound of the invention, or apharmaceutically acceptable salt thereof; preferably, from about 0.7 mgto about 10 mg/kg of body weight per day; and most preferably, fromabout 1.4 mg to about 7.2 mg/kg of body weight per day. For example, foradministration to a 70 kg person, the dosage range would be from about10 mg to about 1.0 gram per day of a compound of the invention, or apharmaceutically acceptable salt thereof, preferably from about 50 mg toabout 700 mg per day, and most preferably from about 100 mg to about 500mg per day.

PREFERRED EMBODIMENTS

[0103] Of the compounds of the invention as set forth above in theSummary of the Invention, a preferred group of compounds are thosecompounds selected from formula (I):

[0104] as single stereoisomers or mixtures thereof; or aspharmaceutically acceptable salts thereof.

[0105] Of this group of compounds, a preferred subgroup of compounds arethose compounds wherein:

[0106] A is —N═;

[0107] Z¹ is —O—, —CH₂O— or —S(O)_(n)— (where n is 1);

[0108] Z² is —O—, —OCH₂— or —S(O)_(n)— (where n is 1);

[0109] R¹ and R⁴ are each independently hydrogen, halo, alkyl or —OR⁹;

[0110] R² is —C(NH)NH₂—, —C(NH)N(H)S(O)₂R¹¹ or —C(NH)N(H)C(O)N(H)R⁹;

[0111] R³ is ureido, guanidino, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl) or (1,2)-imidazolinyl(optionally substituted by alkyl);

[0112] R⁵ and R⁶ are independently hydrogen, halo, alkyl or haloalkyl;

[0113] R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where:

[0114] p is 0 to 5;

[0115] X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—;

[0116] and each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—NOR⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—NOR⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2);

[0117] each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); and

[0118] each R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl).

[0119] Of this subgroup of compounds, a preferred class of compounds arethose compounds wherein:

[0120] A is —N═;

[0121] Z¹ is —O—;

[0122] Z² is —O—;

[0123] R¹ is hydrogen or —OR⁹;

[0124] R² is —C(NH)NH₂;

[0125] R³ is (1,2)-tetrahydropyrimidinyl (optionally substituted bymethyl), (1,2)-imidazolyl (optionally substituted by methyl) or(1,2)-imidazolinyl (optionally substituted by methyl);

[0126] R⁴ is hydrogen;

[0127] R⁵ and R⁶ are each halo;

[0128] R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where:

[0129] p is 0 to 5;

[0130] X is —O—;

[0131] and each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—NOR⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2);

[0132] each R⁹ and R¹⁰ is independently hydrogen or alkyl; and

[0133] each R¹¹ is alkyl or aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl).

[0134] Of this class of compounds, a preferred subclass of compounds arethose compounds wherein:

[0135] A is —N═;

[0136] Z¹ is —O—;

[0137] Z² is —O—;

[0138] R¹ is —OR⁹;

[0139] R² is —C(NH)NH₂;

[0140] R³ is (1,2)-imidazolyl (optionally substituted by methyl) or(1,2)-imidazolinyl (optionally substituted by methyl);

[0141] R⁴ is hydrogen;

[0142] R⁵ and R⁶ are both fluoro;

[0143] R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where:

[0144] p is 0 to 5;

[0145] X is —O—;

[0146] and each R¹³ is independently [C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where eachn is independently 0 to 2); and

[0147] each R⁹ and R¹⁰ is independently hydrogen or alkyl.

[0148] Of this subclass of compounds, preferred compounds are thosecompounds wherein R⁷ is —O—CH₂—C(OH)H—C(OH)H₂.

[0149] Of the preferred group of compounds of formula (I) as describedabove, another preferred subgroup of compounds are those compoundswherein:

[0150] A is —N═;

[0151] Z¹ is —O—, —CH₂O— or —S(O)_(n)— (where n is 0 to 2);

[0152] Z² is —O—, —OCH₂— or S(O)r (where n is 0 to 2);

[0153] R¹ and R⁴ are each independently hydrogen, halo or —OR⁹;

[0154] R² is —C(NH)NH₂, —C(NH)N(H)S(O)₂R¹¹ or —C(NH)N(H)C(O)N(H)R⁹;

[0155] R³ is ureido, guanidino, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

[0156] R⁵ and R⁶ are independently hydrogen, halo, alkyl or haloalkyl;

[0157] R⁷ is selected from the group consisting of the followingformulae:

[0158] where

[0159] q is 0 to 4;

[0160] p is 0 to 5;

[0161] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—NOR⁹)R¹⁰,—(CH₂)_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0162] each R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where:

[0163] each r is independently 0 to 5, and

[0164] each X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; and

[0165] each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2);

[0166] each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl);

[0167] each R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl).

[0168] Of this subgroup of compounds, a preferred class of compounds arethose compounds wherein:

[0169] A is —N═;

[0170] Z¹ is —O—;

[0171] Z² is —O—;

[0172] R¹ is hydrogen or —OR⁹;

[0173] R² is —C(NH)NH₂;

[0174] R³ is (1,2)-tetrahydropyrimidinyl (optionally substituted bymethyl), (1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl);

[0175] R⁴ is hydrogen;

[0176] R⁵ and R⁶ are each halo;

[0177] R⁷ is selected from the group consisting of the followingformulae:

[0178] where

[0179] q is 0 to 4;

[0180] p is 0 to 5;

[0181] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0182] each R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where:

[0183] each r is independently 0 to 5, and

[0184] each X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; and

[0185] each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2);

[0186] each R⁹ and R¹⁰ is independently hydrogen or alkyl; and

[0187] each R¹¹ is independently alkyl or aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl).

[0188] Of this class of compounds, a preferred subclass of compounds arethose compounds wherein:

[0189] A is —N═;

[0190] Z¹ is —O—;

[0191] Z² is —O—;

[0192] R¹ is —OR⁹;

[0193] R² is —C(NH)NH₂;

[0194] R³ is (1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl);

[0195] R⁴ is hydrogen;

[0196] R⁵ and R⁶ are both fluoro;

[0197] R⁷ is selected from the group consisting of the followingformulae:

[0198] where

[0199] q is 0 to 4;

[0200] p is 0 to 5;

[0201] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0202] each R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where:

[0203] each r is independently 0 to 5, and

[0204] each X is independently —O—, —S(O)_(n)— (where n is 0 to 2), or—N(R⁹)—; and

[0205] each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or [CH₂]_(n)—N(R⁹)R¹⁰; and each R⁹and R¹⁰ is independently hydrogen or alkyl

[0206] Of this subclass of compounds, a preferred set of compounds arethose compounds wherein R⁷ is:

[0207] where

[0208] q is 0 to 4;

[0209] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0210] each R¹⁴ is —X[CH₂]_(r)— or —X—CH₂[C(R¹³)H]_(r)—, where:

[0211] each r is independently 0 to 5, and

[0212] each X is independently —O—, —S(O)_(n)— (where n is 0 to 2), or—N(R⁹)—; and

[0213] each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰; and

[0214] each R⁹ and R¹⁰ is independently hydrogen or alkyl.

[0215] Of this set of compounds, a preferred subset of compounds arethose compounds wherein R⁷ is:

[0216] where

[0217] q is 0 to 4;

[0218] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each nis independently 0 to 2); and

[0219] each R¹⁴ is —X—[CH₂]_(r)— where:

[0220] r is 0 to 5, and

[0221] X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; and

[0222] each R⁹ and R¹⁰ is independently hydrogen or alkyl.

[0223] Of this subset of compounds, preferred compounds are thosecompounds wherein:

[0224] where

[0225] q is 0 to 4;

[0226] each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to4), —[CH₂]_(n)—OR⁹ or —[CH₂]_(n)—NOR⁹)R¹⁰ (where each n is independently0 to 2); and

[0227] each R¹⁴ is —X—[CH₂]_(r)— where:

[0228] r is 0 or 1, and

[0229] X is —O—; and

[0230] each R⁹ and R¹⁰ is independently hydrogen or alkyl.

[0231] Of these preferred compounds, even more preferred compounds arethose compounds wherein R⁷ is:

[0232] where R¹⁴ is —O—; q is 3 and one R¹³ is in the 4-position of thetetrahydrofuranyl ring and is hydroxy, the second R¹³ is in the2-position of the tetrahydrofuranyl ring and is 2,3-dihydroxyethyl andthe third R¹³ is in the 5-position of the tetrahydrofuranyl ring and isethoxy.

[0233] Of the preferred compounds of the invention, the most preferredcompounds are the following:

[0234]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy-4-[[2-(1,2-dihydroxyethyl)-4-hydroxy-5-ethoxytetrahydrofuran-3-yl]oxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine;and

[0235]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dihydroxypropoxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine.

PREPARATION OF COMPOUNDS OF THE INVENTION

[0236] As a matter of convenience, the following description of thepreparation of the compounds of the invention is directed to thepreparation of compounds of formula (I) where A is —N═, Z¹ and Z² areboth —O—, and R² is —C(NH)NH₂. It is understood, however, that similarsynthetic processes may be used to prepare other compounds of formula(I), (II), (III), (IV), (V), (VI), and (VII). It is also understood thatin the following description, combinations of substituents and/orvariables (e.g., R⁹ and R¹⁰) on the depicted formulae are permissibleonly if such combinations result in stable compounds.

Preparation of Compounds of Formula (Ia)

[0237] Compounds of formula (Ia) are compounds of Formula (I) of theinvention wherein A is —N═, Z¹ and Z² are both —O—, and R² is —C(NH)NH₂.They are prepared as shown in the following REACTION SCHEME wherein R¹,R², R³, R⁴, R⁵, R⁶ and R⁷ are as described above in the Summary of theInvention, except that prior to Step 1, compounds of formula (B) whichcontain additional reactive hydroxy or amino groups may be treated withthe appropriate oxygen or nitrogen-protecting groups according tomethods known to those skilled in the art, such as those described inGreene, T. W, Protective Groups in Organic Synthesis (1981), John Wiley& Sons, New York. Such protected compounds will be deprotected duringthe reaction conditions of Step 4 to form the desired R⁷ substituent.Alternatively, compounds of formula (B) may already be present in anoxygen or nitrogen-protected form and as a result of the reactionconditions of Step 4 may become deprotected to form the desired R⁷substituent.

[0238] Compounds of formula (A), (B), (D), and (F) are commerciallyavailable, for example, from Aldrich Chemical Co., Sigma Chemical Co.,or ICN Biomedicals, Inc, or may be prepared according to methods knownto those skilled in the art. Compounds of formula (B) are alsocommercially available in protected forms, for example, from AldrichChemical Co. or Sigma Chemical Co.

[0239] In general, the compounds of formula (Ia) are prepared by firsttreating a compound of formula (A) with a compound of formula (B) in anaprotic solvent, for example, DMSO, in the presence of a base, forexample, cesium carbonate, at 0° C. to 80° C., preferably between 25° C.to 60° C., for about 20 to 40 hours. The compound of formula (C) is thenisolated from the reaction mixture by standard techniques, such asextraction, filtration and in vacuo removal of solvent.

[0240] The resulting compound of formula (C) in an aprotic solvent, forexample, acetonitrile, is treated with an equimolar amount of a compoundof formula (D) in the presence of a base, for example, cesium carbonate,at temperatures between about 20° C. and 120° C., preferably at ambienttemperature, for a period of time sufficient to complete the desiredreaction as monitored by thin layer chromatography (TLC). The compoundof formula (E) is then isolated from the reaction mixture by standardisolation techniques, such as extraction, in vacuo removal of solvent,and flash chromatography.

[0241] The compound of formula (E) in an aprotic solvent, for example,DMSO, is then treated with an equimolar amount of a compound of formula(F) in the presence of a base, for example, cesium carbonate, attemperatures between about 20° C. and 120° C., preferably at about 55°C., for a period of time sufficient to complete the desired reaction,for example, for about 24 hours. The reaction mixture is cooled toambient temperature and the compound of formula (G) is then isolatedfrom the reaction mixture through standard isolated techniques, such asextraction, in vacuo removal of solvent, and flash chromatography.

[0242] The compound of formula (G) is dissolved in an anhydrous alkanol,preferably ethanol, and then anhydrous mineral acid, preferably HCl, isadded to the solution over a period of time sufficient to incorporatethe acid into the solution while maintaining the reaction temperaturesat about 78° C. After incorporation is complete, the reaction vessel issealed and the reaction mixture is allowed to warm to ambienttemperature and stirred between 12 and 24 hours, preferably for about 16hours. The solvent is removed in vacuo and the resulting residue isdissolved in fresh anhydrous alkanol, preferably ethanol, and thentreated with anhydrous ammonia (gas) at temperatures from betweenambient temperature and about 100° C. from about 1 to about 48 hours,preferably at about 60° C. and for about 2 hours. The compound offormula (Ia) is then isolated from the reaction mixture by standardisolation techniques, for example, in vacuo removal of solvent andpurification by high performance liquid chromatography (HPLC). Duringthis last step, compounds of formula (G) where R⁷ is in an oxygen ornitrogen protected form are deprotected to form compounds of formula(Ia) where R⁷ is as defined above in the Summary of the Invention.

[0243] Alternatively, instead of treating the resulting residue abovewith anhydrous ammonia (gas), the resulting residue may be treated witha compound of the formula NH₂OR⁹ to afford the corresponding compound offormula (Ia) wherein R² is —C(NH)N(H)OR⁹.

[0244] Compounds of formula (Ia) wherein R³ is —C(NH)NH₂ or—C(NH)N(H)OR⁹ are produced from the corresponding cyano compounds in asimilar manner as that described above for compound of formula (G).

[0245] Compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵, R⁶, R⁹, R¹⁰ orR¹¹ contains an alkoxycarbonyl group or a C(O)OR⁹ group where R⁹ isalkyl or aralkyl may also be treated under standard transesterificationconditions with an alcohol of the formula R⁹OH where R⁹ is aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) toproduce compounds of the invention wherein R¹, R³, R⁴, R⁵, R⁶, R⁹, R¹⁰or R¹¹ contains an aryloxycarbonyl group or a —C(O)OR⁹ group where R⁹ isaryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).

[0246] Compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, orR¹¹ contains an aminocarbonyl group, a monoalkylaminocarbonyl group, adialkylaminocarbonyl group, a —C(O)N(R⁹)R¹⁰ group or a —C(O)OR⁹ group(where each R⁹ or R¹⁰ is independently alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl)) may also be hydrolyzed under acidic conditions toprepare corresponding compounds of the invention where R¹, R³, R⁴, R⁵,R⁶, R⁹, R¹⁰, or R¹¹ contains a carboxy or a —C(O)OH group.

[0247] Compounds of formula (la) wherein R¹, R³, R⁴, R⁵, R⁶, R⁹, R¹⁰ orR¹¹ contains a carboxy group, an alkoxycarbonyl group, or a —C(O)OR⁹group where R⁹ is hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl), or optionally substituted aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) may alsobe amidated under standard amidation conditions to form thecorresponding compounds of formula (Ia) where R¹, R³, R⁴, R⁵, R⁶, R⁹,R¹⁰, or R¹¹ contains an aminocarbonyl group, a monoalkylaminocarbonylgroup, a dialkylaminocarbonyl group or a —C(O)N(R⁹)R¹⁰ group where R⁹and R¹⁰ are independently hydrogen, alkyl, aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or optionallysubstituted aralkyl (optionally substituted by halo, alkyl, aryl,hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl).

[0248] Compounds of formula (Ia) where R¹, R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, orR¹¹ contains a nitro group may also be reduced under standard conditionsto produce the corresponding compounds of formula (Ia) where R¹, R³, R⁴,R⁵, R⁶, R⁹, R¹⁰, or R¹¹ contains an amino group, which may also betreated with the appropriate alkylating agents or acylating agents toafford the corresponding compounds of formula (Ia) where R¹, R³, R⁴, R⁵,R⁶, R⁹, R¹⁰, or R¹¹ contains a monoalkylamino group, a dialkylaminogroup, a —N(R⁹)R¹⁰ group or a —N(R⁹)C(O)R⁹ where each R⁹ and R¹⁰ isindependently hydrogen, alkyl, or aralkyl (optionally substituted byhalo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl).

[0249] Compounds of formula (Ia) may also be further treated with theappropriate acid halide, preferably acid chloride, or with theappropriate acid anhydride or an equivalent, to yield compounds of theinvention wherein R² is —C(NH)N(H)C(O)R⁹ where R⁹ is hydrogen, alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oroptionally substituted aralkyl (optionally substituted by halo, alkyl,aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl).

[0250] Alternatively, compounds of formula (la) may further be treatedwith carbamoyl chlorides or their equivalents to yield compounds of theinvention where R² is —C(NH)N(H)C(O)OR⁹ where R⁹ is hydrogen, alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oroptionally substituted aralkyl (optionally substituted by halo, alkyl,aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl).

[0251] Alternatively, compounds of formula (Ia) may also be furthertreated with compounds of the formula R¹¹—S(O)₂imidazole (where R¹¹ isdefined above in the Summary of the Invention) in a polar solvent, suchas methylene chloride, at ambient temperature to afford compounds of theinvention where R² is —C(NH)N(H)S(O)₂R¹¹ where R¹¹ is defined above inthe Summary of the Invention.

[0252] Alternatively, compounds of formula (Ia) may be further treatedwith an appropriately N-R⁹-substituted phenylcarbamate in a polarsolvent, preferably methylene chloride, at ambient temperature, forabout 6 to 24 hours, preferably for about 12 hours, to afford compoundsof the invention where R²is —C(NH)N(H)C(O)N(H)R⁹ where R⁹ is definedabove in the Summary of the Invention.

[0253] Compounds of formula (Ia) which contain an unoxidized sulfur atommay be oxidized with the appropriate oxidizing agent to producecompounds containing oxidized sulfur (i.e., —S(O)_(n)— where n is 1 or2).

[0254] The following specific preparations and examples are provided asa guide to assist in the practice of the invention, and are not intendedas a limitation on the scope of the invention.

PREPARATION 1 Compounds of Formula (C)

[0255] A. To pentafluoropyridine (2.0 g, 12 mmol) dissolved in DMSO wasadded 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (1.5 mL, 12 mmol)and Cs₂CO₃ (3.8 g, 12 mmol). The slurry was heated in an oil bath at 60°C. for 1 day. The reaction was partitioned with water and ethyl acetate,washed with water and brine, dried (Na₂SO₄) and the solvent was removedto give2,3,5,6-tetrafluoro-4-[[(2,2-dimethyl)dioxolan-4-yl]methoxy]pyridine(3.2 g).

[0256] B. In a similar manner, the following compound of formula (C) wasprepared:

[0257]2,3,5,6-tetrafluoro-4-[[5-[(2,2-dimethyl)dioxolan-4-yl]-3a,5,6,6a-tetrahydrofuro[2,3-d]-1,3-dioxol-6-yl]oxy]pyridine.

[0258] C. In a similar manner, the following oxygen ornitrogen-protected compounds of formula (C) are prepared:

[0259]2,3,5,6-tetrafluoro-4-[2-(acetyl)amino-4-(methylthio)but-1-oxy]pyridine;

[0260]2,3,5,6-tetrafluoro-4-[(2-(acetyl)amino-3-hydroxyprop-1-yl)thio]pyridine;

[0261]2,3,5,6-tetrafluoro-4-[[2′,2′,2,2tetramethyl-3a′,4′,7′,7a′-tetrahydrospiro[1,3-doxolane-4,6′-[6H-1,3]dioxolo[4,5-c]pyran-7′-yl]]oxy]pyridine;

[0262]2,3,5,6-tetrafluoro-4-[(4-methoxy-2,2-dimethyl-6-(trityloxy)methyl-3a,6,7,7a-tetrahydro-4H-1,3-dioxolo[4,5-c]pyran-7-yl)oxy]pyridine;

[0263]2,3,5,6-tetrafluoro-4-[(2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-dioxolan-4-yl)methoxy]pyridine;

[0264]2,3,5,6-tetrafluoro-4-[bis(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridine;

[0265]2,3,5,6-tetrafluoro-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-3a-yl)methoxy]pyridine;

[0266]2,3,5,6-tetrafluoro-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy]pyridine;

[0267]2,3,5,6-tetrafluoro-4-[(6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d]-1,3-dioxol-4-yl)methoxy]pyridine;and

[0268]2,3,5,6-tetrafluoro-4-[(5-(((methoxycarbonyl)oxy)methyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d]-1,3-dioxol-6-yl)oxy]pyridine.

[0269] D. In a manner similar to that described above, other compoundsof formula (C) may be prepared.

PREPARATION 2 Compounds of Formula (E)

[0270] A. To2,3,5,6-tetrafluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridine (3.2g, 11 mmol) in CH₃CN (20 mL) was added Cs₂CO₃ (3.8 g, 12 mmol) and3-hydroxy-4-(benzyloxy)benzonitrile (2.5 g, 11 mmol). After stirring for24 hours the reaction was partitioned with water and ethyl acetate. Thelayers were separated, washed with water and brine, dried (Na₂SO₄), andthe solvent was removed in vacuo. The residue was triturated withhexane/ethyl acetate (1/1) and the resulting solid was collected byfiltration to give3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile(3.0 g).

[0271] B. In a similar manner, the following compound of formula (E) wasprepared:

[0272]3-[[3,5,6-trifluoro-4-[[5-[(2,2-dimethyl)dioxolan-4-yl]-3a,5,6,6a-tetrahydrofuro[2,3-d]-1,3-dioxol-6-yl]oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile.

[0273] C. In a similar manner, the following oxygen ornitrogen-protected compounds of formula (E) are prepared:

[0274]3-[[3,5,6-trifluoro-4-[2-(acetyl)amino-4-(methylthio)but-1-oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0275]3-[[3,5,6-trifluoro-4-[(2-(acetyl)amino-3-hydroxyprop-1-yl)thio]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0276]3-[[3,5,6-trifluoro-4-[[2′,2′,2,2-tetramethyl-3a′,4′,7′,7a′-tetrahydrospiro[1,3-doxolane-4,6′-[6H-1,3]dioxolo[4,5-c]pyran-7′-yl]]oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0277]3-[[3,5,6-trifluoro-4-[(4-methoxy-2,2-dimethyl-6-(trityloxy)methyl-3a,6,7,7a-tetrahydro-4H-1,3-dioxolo[4,5-c]pyran7yl)oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0278]3-[[3,5,6-trifluoro-4-[(2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-dioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0279]3-[[3,5,6-trifluoro-4-[bis(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0280]3-[[3,5,6-trifluoro-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran3a-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0281]3-[[3,5,6-trifluoro-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0282]3-[[3,5,6-trifluoro-4-[(6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d]-1,3-dioxol-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;and

[0283]3-[[3,5,6-trifluoro-4-[(5-(((methoxycarbonyl)oxy)methyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d]1,3dioxol-6-yl)oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile.

[0284] D. In a manner similar to that described above, other compoundsof formula (E) may be prepared.

PREPARATION 3 Compounds of Formula (G)

[0285] A. To3-[[3,5,6-trifluoro-4-[(2,2-dimethyidioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile(1.0 g, 2.1 mmol) in DMSO (6 mL) was added Cs₂CO₃ (0.7 g, 2.1 mmol) and2-(3-hydroxyphenyl)-1-methylimidazoline (0.4 g, 2.2 mmol). Afterstirring in an oil bath at 55° C. for 24 hours, the reaction waspartitioned with water and ethyl acetate. The layers were separated,washed with water and brine, dried (Na₂SO₄), and the solvent was removedin vacuo. The residue was chromatographed on silica withCH₂Cl₂/MeOH/NH₄OH (240/10/1) to give3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile(0.9 g).

[0286] B. In a similar manner, the following compound of formula (G) wasprepared:

[0287]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[[5-[(2,2-dimethyl)dioxolan-4-yl]-3a,5,6,6a-tetrahydrofuro[-2,3-d]-1,3-dioxol-6-yl]oxy]pyridin2yl]oxy]-4-(benzyloxy)benzonitrile.

[0288] C. In a similar manner, the following oxygen-protected ornitrogen-protected compounds of formula (G) are prepared:

[0289]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[2-(acetyl)amino-4-(methylthio)but-1-oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0290]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2-(acetyl)amino-3-hydroxyprop-1-yl)thio]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0291]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[[2′,2′,2,2-tetramethyl-3a′,4′,7′,7a′-tetrahydrospiro[1,3-doxolane-4,6′-[6H-1,3]dioxolo[4,5-c]pyran-7′-yl]]oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0292]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(4-methoxy-2,2-dimethyl-6-(trityloxy)methyl-3a,6,7,7a-tetrahydro-4H-1,3-dioxolo[4,5-c]pyran-7-yl)oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0293]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-dioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0294]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[bis(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0295]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-3a-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0296]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2,7,7-tetramethyl-3a,5a,8a,8b-tetrahydro-5H-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;

[0297]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d]-1,3-dioxol-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile;and

[0298]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(5-(((methoxycarbonyl)oxy)methyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d]-1,3-dioxol-6-yl)oxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile.

[0299] D. In a manner similar to that described above, other compoundsof formula (G) may be prepared.

EXAMPLE Compounds of Formula (I)

[0300] A. To3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4[-(2,2-dimethyidioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile(0.9 g, 1.4 mmol), dissolved in ethanol (6 mL) and cooled in a dryice/isopropanol bath, was bubbled HCl (g). After the solution wassaturated, the reaction flask was sealed and the reaction mixture wasallowed to warm to ambient temperature and was stirred for 18 hours. Thesolvent was removed in vacuo and the residue was triturated with ether.The ether was decanted off and the residue was dissolved in ethanol (6mL). The solution was cooled in a dry ice/isopropanol bath and ammonia(g) was bubbled into the solution. The reaction flask was sealed andheated in an oil bath at 60° C. for 2 hours. The solvent was removed invacuo and the residue was purified by HPLC on a C18 Dynamax column witha 10-40% acetonitrile in water gradient with 0.1% trifluoroacetic acidto give 0.76 g of3-[[-3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dihydroxypropoxy)pyridin-2-yl]oxy]4-hydroxybenzamidineas a pure trifluoroacetic acid salt; NMR (DMSO-d₆) 10.2 (s,2), 9.0(s,2), 8.9 (s,2), 7.5 (m,3), 7.4 (m,3), 7.0 (d,1), 4.55 (m,1), 4.4(m,1), 4.0 (m,2), 3.9 (m,2), 3.8 (m,1), 3.45 (d,2), 2.95 (s,3) ppm.

[0301] B. In a similar manner, the following compound of formula (I) wasmade:

[0302]3-[[-3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[[2-(1,2-dihydoxyethyl)-4-hydroxy-5-ethoxytetrahydrofuran-3-yl]oxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 10.3 (s,1), 9.0(s,2), 8.9 (s,2), 7.5 (m,3), 7.3 (m,3), 7.0 (d,1), 5.5 (m,1), 5.3 (m,1),4.75 (m,2), 4.0 (m,2), 3.85 (m,2), 3.6 (m,4), 3.5 (m,3), 2.92 (s,3),1.12 (t,3) ppm.

[0303] C. In a similar manner, the following compounds of the inventionare prepared:

[0304]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-amino-4-(methylthio)but-1-oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0305]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-amino-3-hydroxyprop-1-yl)thio)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0306]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((4,5-dihydroxy-2-ethoxy-2-(hydroxymethyl)tetrahydropyran-3-yl)oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0307]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((4,5-dihydroxy-2-hydroxymethyl-6-ethoxytetrahydropyran-3-yl)oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0308]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2,3,4,5-tetrahydroxypent-1-yl)oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0309]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1,2,4,5-tetrahydroxypent-3-yl)oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0310]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2-ethoxy-3,4,5-trihydroxytetrahydropyran-2-yl)methoxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0311]3-[[3,5-difluoro6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(6-ethoxy-3,4,5-trihydroxytetrahydropyran-2-yl)methoxy]pyridine-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt;

[0312]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(3,4-dihydroxy-5-ethoxytetrahydrofuran-2-yl)methoxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt; and

[0313]3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(5-ethoxy-4-hydroxy-2-hydroxymethyltetrahydrofuran-3-yl)oxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine,trifluoroacetic acid salt.

[0314] D. In a manner similar to that described above, other compoundsof the invention may be prepared.

EXAMPLE 2

[0315] This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[[2-(1,2-dihydoxyethyl)-4-hydroxy-5-ethoxytetrahydrofuran-3-yl]oxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine:A. Ingredients % wt./wt. Compound of the invention 20.0% Lactose 79.5%Magnesium stearate 0.5%

[0316] The above ingredients are mixed and dispensed into hardshellgelatin capsules containing 100 mg each, one capsule would approximate atotal daily dosage. B. Ingredients % wt./wt. Compound of the invention20.0% Magnesium stearate 0.9% Starch 8.6% Lactose 69.6% PVP(polyvinylpyrrolidine) 0.9%

[0317] The above ingredients with the exception of the magnesiumstearate are combined and granulated using water as a granulatingliquid. The formulation is then dried, mixed with the magnesium stearateand formed into tablets with an appropriate tableting machine. C.Ingredients Compound of the invention  0.1 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80  1.0 g Water q.s. 100 mL

[0318] The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled. D. Ingredients % wt./wt. Compound of theinvention 20.0% Peanut Oil 78.0% Span 60 2.0%

[0319] The above ingredients are melted, mixed and filled into softelastic capsules. E. Ingredients % wt./wt. Compound of the invention1.0% Methyl or carboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

[0320] The compound of the invention is dissolved in thecellulose/saline solution, filtered and bottled for use.

EXAMPLE 3

[0321] This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dihydroxypropoxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine:Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80  1.0 g 0.9% Salinesolution q.s. 100 mL

[0322] The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 m membrane filter andpackaged under sterile conditions.

EXAMPLE4

[0323] This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dihydroxypropoxy)pyridin-2yl]oxy]-4-hydroxybenzamidine:Ingredients % wt./wt. Compound of the invention 1.0% Polyethylene glycol1000 74.5% Polyethylene glycol 4000 24.5%

[0324] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight.

EXAMPLE 5

[0325] This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,3-[[3,4-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-amino-4-(methylthio)but-1-oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine:Ingredients % wt./wt. Micronized compound of the invention 1.0%Micronized lactose 99.0%

[0326] The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 6

[0327] This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,3-[[3,4-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-amino-4-(methylthio)but-1-oxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine:Ingredients % wt./wt. Compound of the invention 0.005% Water 89.995%Ethanol 10.000%

[0328] The compound of the invention is dissolved in ethanol and blendedwith water. The formulation is then packaged in a nebulizer equippedwith a dosing pump.

EXAMPLE 7

[0329] This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,3-[[3,4-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-amino-3-hydroxyprop-1-yl)thio)pyridin-2-yl]oxy]-4-hydroxybenzamidine:Ingredients % wt./wt. Compound of the invention 0.10% Propellant 11/1298.90% Oleic acid 1.00%

[0330] The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 8 (In vitro assay for Factor Xa and Thrombin)

[0331] This assay demonstrates the activity of the compounds of theinvention towards factor Xa, thrombin and tissue plasminogen activator.The activities were determined as an initial rate of cleavage of thepeptide p-nitroanilide by the enzyme. The cleavage product,p-nitroaniline, absorbs at 405 nm with a molar extinction coefficient of9920 M⁻¹cm¹.

[0332] Reagents and Solutions:

[0333] Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

[0334] Assay buffer:

[0335] 50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, and

[0336] 0.1% polyethylene glycol 6000, pH 7.5.

[0337] Enzymes (Enzyme Research Lab.):

[0338] 1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer,stored at −80° C. (working solution (2×): 106 ng/mL or 2 nM in assaybuffer, prepare prior to use).

[0339] 2. Human thrombin stock solution: Concentration as specified bythe supplier, stored at −80° C. (working solution (2×): 1200 ng/mL or 32nM in assay buffer, prepare prior to use).

[0340] 3. Human tissue plasminogen activator (tPA) (Two chains, Sigma orAmerican Diagnostica Inc.) stock solution: Concentration as specified bythe supplier, stored at −80° C. (working solution (2×): 1361 ng/mL or 20nM in assay buffer, prepare prior to use).

[0341] Chromogenic substrates (Pharmacia Hepar Inc.):

[0342] 1. S2222 (FXa assay) stock solution: 6 mM in deionized H₂O, storeat 4° C. (working solution (4×): 656 μM in assay buffer).

[0343] 2. S2302 (Thrombin assay) stock solution: 10 mM in deionized H₂O,stored at 4° C. (working solution (4×): 1200 μM in assay buffer).

[0344] 3. S2288 (tPA assay) stock solution: 10 mM in deionized H₂O,stored at 4° C. (working solution (4×): 1484 μM in assay buffer forSigma tPA, or 1120 μM for American Diagnostica tPA).

[0345] Standard inhibitor compound stock solution:

[0346] 5 mM in DMSO, stored at −20° C.

[0347] Test compounds (compounds of the invention) stock solutions:

[0348] 10 mM in DMSO, stored at −20° C.

[0349] Assay procedure:

[0350] Assays were performed in 96well microtiter plates in a totalvolume of 200 μl. Assay components were in final concentration of 50 mMTrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH7.5, in the absence or presence of the standard inhibitor or the testcompounds and enzyme and substrate at following concentrations: (1) 1 nMfactor Xa (0.1nM or 0.2 nM factor Xa for compounds with K_(i)Xa in lowpicomolar range) and 164 μM S2222; (2) 16 nM thrombin and 300 μM S2302;and (3) 10 nM tPA and 371 μM or 280 μM S2288. Concentrations of thestandard inhibitor compound in the assay were from 5 μM to 0.021 μM in 1to 3 dilution. Concentration of the test compounds in the assaytypically were from 10 μM to 0.041 μM in 1 to 3 dilution. For potenttest compounds, the concentrations used in the factor Xa assay werefurther diluted 100 fold (100 nM to 0.41 nM) or 1000 fold (10 nM to0.041 nM). All substrate concentrations used are equal to their K_(m)values under the present assay conditions. Assays were performed atambient temperature.

[0351] The first step in the assay was the preparation of 10 mM testcompound stock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4×) by a serial dilutions of 10 mM stock solutions with Biomek 1000 in96 deep well plates as follows:

[0352] (a) Prepare a 40 μM working solution by diluting the 10 mM stock1 to 250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

[0353] (b) Make another five serial dilutions (1:3) of the 40 μMsolution (600 μL for each concentration). A total of six diluted testcompound solutions were used in the assay. Standard inhibitor compound(5 mM stock) or DMSO (control) went through the same dilution steps asthose described above for test compounds.

[0354] The next step in the assay was to dispense 50 μL of the testcompound working solutions (4×) (from 40 μM to 0.164 μM) in duplicate tomicrotiter plates with Biomek. To this was added 100 μL of enzymeworking solution (2×) with Biomek. The resulting solutions wereincubated at ambient temperature for 10 minutes.

[0355] To the solutions was added 50 μL of substrate working solution(4×) with Biomek.

[0356] The enzyme kinetics were measured at 405 nm at 10 secondsintervals for five minutes in a THERMOmax plate reader at ambienttemperature. When a lower concentration of factor Xa was needed in thefactor Xa assay, the enzyme kinetics were measured for fifteen minutes(0.2 nM factor Xa) or thirty minutes (0.1 nM factor Xa) at ambienttemperature.

[0357] Calculation of K_(i) of the Test compounds:

[0358] Enzyme initial rates were calculated as mOD/min based on thefirst two minutes readings. The IC₅₀ values were determined by fittingthe data to the log-logit equation (linear) or the Morrison equation(nonlinear) with an EXCEL spreadsheet. K_(i) values were then obtainedby dividing the IC₅₀ by 2. Routinely, K. (factor Xa) values less than 3nM were calculated from the Morrison equation.

[0359] Compounds of the invention, when tested in this assay,demonstrated the selective ability to inhibit human factor Xa and humanthrombin.

EXAMPLE 9 (In vitro assay for Human Prothrombinase)

[0360] This assay demonstrates the ability of the compounds of theinvention to inhibit prothrombinase. Prothrombinase (PTase) catalyzesthe activation of prothrombin to yield fragment 1.2 plus thrombin withmeizothrombin as the intermediate. This assay is an end point assay.Activity of the prothrombinase is measured by activity of thrombin (oneof the reaction products) or by the amount of thrombin formed/time basedon a thrombin standard curve ( nM vs mOD/min). For determination of IC₅₀(PTase) of the compounds of the invention, PTase activity was expressedby thrombin activity (mOD/min).

[0361] Materials:

[0362] Enzymes:

[0363] 1. Human factor Va (Haematologic Technologies Inc., Cat#HCVA0110) working solution:

[0364] 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at −20° C.

[0365] 2. Human factor Xa (Enzyme Res. Lab. cat# HFXa1011) workingsolution: 0.281 mg/mL in assay buffer (without BSA), stored at −80° C.

[0366] 3. Human prothrombin (FII) (Enzyme Res. Lab., Cat# HP1002)working solution: Diluted FII to 4.85 mg/mL in assay buffer (withoutBSA), stored at −80° C.

[0367] Phospholipid (PCPS) vesicles:

[0368] PCPS vesicles (80%PC, 20%PS) were prepared by modification of themethod reported by Barenholz et al., Biochemistry (1977), Vol. 16, pp.2806-2810.

[0369] Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032):

[0370] 10 mg/mL in chloroform, purified from brain, stored −20° C. undernitrogen or argon.

[0371] Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat# 850457):

[0372] 50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl,stored at −20° C. under nitrogen or argon.

[0373] Spectrozyme-TH (American Diagnostica Inc., Cat# 238L, 50 μmoles,stored at ambient temperature) working solution: Dissolved 50 μmoles in10 mL dH₂O.

[0374] BSA (Sigma Chem Co., Cat# A7888, FractionV, RIA grade).

[0375] Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂,0.1% PEG 6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

[0376] For one plate assay, prepare the following working solutions:

[0377] 1. Prothrombinase complex:

[0378] (a) 100 μM PCPS (27.5 μL of PCPS stock (4.36 mM) diluted to final1200 μL with assay buffer.

[0379] (b) 25 nM Human factor Va: 5.08 μL of Va stock (1 mg/mL) wasdiluted to final 1200 μL with assay buffer.

[0380] (c) 5 μM Human factor Xa: Dilute factor Xa stock (0.281 mg/mL)1:1,220,000 with assay buffer. Prepare at least 1200 μL.

[0381] Combine equal volumes (1100 μL) of each component in the order ofPCPS, Va and Xa. Use immediately or store in ice (bring to ambienttemperature before use).

[0382] 2. 6 μM Human prothrombin (FII): dilute 124 μL of FII stock (4.85mg/mL) to final 1400 μL with assay buffer.

[0383] 3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus19.2 mL assay buffer.

[0384] 4. 0.2 mM SpectrozymeTH/EDTA buffer: 0.44 mL of SPTH stock (5 mM)plus 10.56 mL of 20 mM EDTA/assay buffer.

[0385] 5. Test compounds (compounds of the invention):

[0386] Prepare a working solution (5×) from 10 mM stock (DMSO) and makea series of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

[0387] Assay conditions and procedure:

[0388] Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 μM PCPS, 5 nM hFVa, and 1 μM hFXa), 1.2 μM humanfactor II and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at ambient temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96well microtiter plates.

[0389] In the first step of the assay, 10 μL of diluted test compound(5×) or buffer was added to the plates in duplicate. Then 10 μL ofprothrombin (hFII) (5×) was added to each well. Next 30 μL PTase wasadded to each well, mix for about 30 seconds. The plates were thenincubated at ambient temperature for 6 minutes.

[0390] In the next step, 50 μL of 20 mM EDTA (in assay buffer) was addedto each well to stop the reaction. The resulting solutions were thenmixed for about 10 seconds. Then 100 μL of 0.2 mM spectrozyme was addedto each well. The thrombin reaction rate was then measured at 405 nm for5 minutes at 10 seconds intervals in a Molecular Devices microplatereader.

[0391] Calculations:

[0392] Thrombin reaction rate was expressed as mOD/min. using ODreadings from the five minute reaction. IC₅₀ values were calculated withthe log-logit curve fit program.

[0393] The compounds of the invention demonstrated the ability toinhibit prothrombinase when tested in this assay.

EXAMPLE 10 (In vivo assay)

[0394] The following assay demonstrates the ability of the compounds toact as anticoagulants.

[0395] Male rats (250-330 g) were anesthetized with sodium pentobarbital(90 mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a midline incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperformed using a Wilcoxin-matched-pairs signed rank test.

[0396] The compounds of the invention, when tested in this assay,demonstrated the ability to inhibit the clotting of the blood.

[0397] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound selected from the group consisting ofthe following formulae:

wherein: A is —C(R⁸)═ or —N═ (where R⁸ is hydrogen, alkyl or halo); Z¹is —O—, —N(R⁹)—, —CH₂O— or —S(O)_(n)— (where n is 0 to 2); Z² is —O—,—N(R⁹)—, —OCH₂— or —S(O)_(n)— (where n is 0 to 2); R¹ and R ⁴are eachindependently hydrogen, halo, alkyl, nitro, —OR⁹, —C(O)OR⁹,—C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or —N(H)S(O)₂R¹¹; R² is—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹¹, —C(NH)N(H)C(O)R⁹,—C(NH)N(H)S(O)₂R¹¹, or —C(NH)N(H)C(O)N(H)R⁹; R³ is hydrogen, halo,alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹, —C(NH)NH₂,—C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹²C(O)N(R⁹)R¹⁰, —CH(OH)C(O)N(R⁹)R¹⁰,—N(R⁹)R¹⁰, —R¹²—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹²—C(O)OR⁹, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁵ and R⁶ areindependently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R⁹)R¹⁰,—C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰, —N(R⁹)C(O)N(R⁹)R¹⁰,—N(R⁹)C(O)R¹⁰, —N(R⁹)S(O)₂R¹¹, or —N(R⁹)C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰; R⁷ is—X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ or —X—C([C(R¹³)H]_(p)—C(R¹³)H₂)₂H where: pis 0 to 5; X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; andeach R¹³ is independently —[C(OR⁹)H]_(m)—CH₂OR⁹ (where m is 1 to 4),—[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —[CH₂]_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); orR⁷ is selected from the group consisting of the following formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —(CH₂)_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); andeach R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where: each r isindependently 0 to 5, and each X is —O—, —S(O)_(n)— (where n is 0 to 2),or —N(R⁹)—; and each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (wherem is 1 to 4), —[CH₂]_(n)OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen,alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); each R¹¹ is alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); and each R¹² is independently an alkylene oralkylidene chain; as a single stereoisomer or a mixture thereof; or apharmaceutically acceptable salt thereof.
 2. The compound of claim Iselected from formula (I):

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 2 wherein: A is —N═;Z¹ is —O—, —CH₂O— or —S(O)_(n)— (where n is 1); Z² is —O—, —OCH₂— or—S(O)_(n)— (where n is 1); R¹ and R⁴ are each independently hydrogen,halo, alkyl or —OR⁹; R² is —C(NH)NH₂, —C(NH)N(H)S(O)₂R¹¹ or—C(NH)N(H)C(O)N(H)R⁹; R³ is ureido, guanidino, N(R⁹)R¹⁰, N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl) or (1,2)-imidazolinyl(optionally substituted by alkyl); R⁵ and R⁶ are independently hydrogen,halo, alkyl or haloalkyl; R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where: pis 0 to 5; X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; andeach R¹³ is independently —[C(OR⁹)H]_(m)—CH₂OR⁹ (where m is 1 to 4),—[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —[CH₂]_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2);each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); and each R¹¹ is alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl).
 4. The compound of claim 3 wherein: A is —N═; Z¹is —O—; Z² is —O—; R¹ is hydrogen or —OR⁹; R² is —C(NH)NH₂; R³ is(1,2)-tetrahydropyrimidinyl (optionally substituted by methyl),(1,2)-imidazolyl (optionally substituted by methyl) or(1,2)-imidazolinyl (optionally substituted by methyl); R⁴ is hydrogen;R⁵ and R⁶ are each halo; R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where: p is0 to 5; X is —O—; and each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹(where m is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹,—[CH₂]_(n)—N(R⁹)R¹⁰, —[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹,—[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)Or¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen oralkyl; and each R¹¹ is alkyl or aryl (optionally substituted by halo,alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl).
 5. The compound of claim 4 wherein: A is —N═;Z¹ is —O—; Z² is —O—; R¹ is —OR⁹; R² is —C(NH)NH₂; R³ is(1,2)-imidazolyl (optionally substituted by methyl) or(1,2)-imidazolinyl (optionally substituted by methyl); R⁴ is hydrogen;R⁵ and R⁶ are both fluoro; R⁷ is —X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ where: pis 0 to 5; X is —O—; and each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each n is independently 0to 2); and each R⁹ and R¹⁰ is independently hydrogen or alkyl.
 6. Thecompound of claim 5 wherein: R⁷ is —O—CH₂—C(OH)H—C(OH)H₂.
 7. Thecompound of claim 6 , namely,3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dihydroxypropoxy)pyridin-2-yl]oxy]-4-hydroxybenzamidine.8. The compound of claim 2 wherein: A is —N═; Z¹ is —O—, —CH₂O— or—S(O)_(n)— (where n is 0 to 2); Z² is —O—, —OCH₂— or —S(O)_(n)— (where nis 0 to 2); R¹ and R⁴ are each independently hydrogen, halo or —OR⁹; R²is —C(NH)NH₂, —C(NH)N(H)S(O)₂R¹¹ or —C(NH)N(H)C(O)N(H)R⁹; R³ is ureido,guanidino, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, (1,2)-tetrahydropyrimidinyl(optionally substituted by alkyl), (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); R⁵ and R⁶ are independently hydrogen, halo, alkyl or haloalkyl;R⁷ is selected from the group consisting of the following formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), [CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —(CH₂)_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); andeach R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where: each r isindependently 0 to 5, and each X is —O—, —S(O)_(n)— (where n is 0 to 2),or —N(R⁹)—; and each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (wherem is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen,alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); each R¹¹ is alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl).
 9. The compound of claim 8 wherein: A is —N═; Z¹is —O—; Z² is —O—; R¹ is hydrogen or —OR⁹; R² is —C(NH)NH₂; R³ is(1,2)-tetrahydropyrimidinyl (optionally substituted by methyl),(1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); R⁴ is hydrogen;R⁵ and R⁶ are each halo; R⁷ is selected from the group consisting of thefollowing formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —(CH₂)_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); andeach R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where: each r isindependently 0 to 5, and each X is —O—, —S(O)_(n)— (where n is 0 to 2),or —N(R⁹)—; and each R¹³ is independently —[CH(OR⁹)]_(m)CH₂—OR⁹ (where mis 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen oralkyl; and each R¹¹ is independently alkyl or aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
 10. Thecompound of claim 9 wherein: A is —N═; Z¹ is —O—; Z² is —O—; R¹ is —OR⁹;R² is —C(NH)NH₂; R³ is (1,2)-imidazolyl (optionally substituted bymethyl), or (1,2)-imidazolinyl (optionally substituted by methyl); R⁴ ishydrogen; R⁵ and R⁶ are both fluoro; R⁷ is selected from the groupconsisting of the following formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each n is independently 0to 2); and each R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where:each r is independently 0 to 5, and each X is independently —O—,—S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; and each R¹³ isindependently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—SR⁹or —[CH₂]_(n)—N(R⁹)R¹⁰; and each R⁹ and R¹⁰ is independently hydrogen oralkyl.
 11. The compound of claim 10 wherein R⁷ is:

where q is 0 to 4; each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹(where m is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or—[CH₂]_(n)—N(R⁹)R¹⁰ (where each n is independently 0 to 2); and each R¹⁴is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where: each r isindependently 0 to 5, and each X is independently —O—, S(O)_(n)— (wheren is 0 to 2), or —N(R⁹); and each R ¹³ is independently—[CH(OR⁹)]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰; and each R⁹ and R¹⁰ isindependently hydrogen or alkyl.
 12. The compound of claim 11 wherein R⁷is:

where q is 0 to 4; each R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹(where m is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹ or—[CH₂]_(n)—N(R⁹)R¹⁰ (where each n is independently 0 to 2); and each R¹⁴is —X—[CH₂]_(r)— where: r is 0 to 5, and X is —O—, —S(O)_(n)— (where nis 0 to 2), or —N(R⁹)—; and each R⁹ and R¹⁰ is independently hydrogen oralkyl.
 13. The compound of claim 12 wherein R⁷ is:

where q is 0 to 4; each R¹³ is independently —[C(OR⁹)H]_(m)CH₂—OR⁹(where m is 1 to 4), —[CH₂]_(n)—OR⁹ or —[CH₂]_(n)—N(R⁹)R¹⁰ (where each nis independently 0 to 2); and each R¹⁴ is —X—[CH₂]_(r)— where: r is 0 or1, and X is —O—; and each R⁹ and R¹⁰ is independently hydrogen or alkyl.14. The compound of claim 13 wherein R⁷ is:

where R¹⁴ is —O—; q is 3 and one R¹³ is in the 4-position of thetetrahydrofuranyl ring and is hydroxy, the second R¹³ is in the2-position of the tetrahydrofuranyl ring and is 2,3-dihydroxyethyl andthe third R¹³ is in the 5-position of the tetrahydrofuranyl ring and isethoxy.
 15. The compound of claim 14 , namely,3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[[2-(1,2-dihydoxyethyl)-4-hydroxy-5-ethoxytetrahydrofuran-3-yl]oxy]pyridin-2-yl]oxy]-4-hydroxybenzamidine.16. A pharmaceutical composition useful in treating a human having adisease-state characterized by thrombotic activity, which compositioncomprises a therapeutically effective amount of a compound selected fromthe group consisting of the following formulae:

wherein: A is —C(R⁶)═ or —N═ (where R⁸ is hydrogen, alkyl or halo); Z¹is —O—, —N(R⁹)—, —CH₂O— or —S(O)_(n)— (where n is 0 to 2); Z² is —O—,—N(R⁹)—, —OCH₂— or —S(O)_(n)— (where n is 0 to 2); R¹ and R⁴ are eachindependently hydrogen, halo, alkyl, nitro, —OR⁹, —C(O)OR⁹,—C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or —N(H)S(O)₂R¹¹; R² is—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹¹, —C(NH)N(H)C(O)R⁹,—C(NH)N(H)S(O)₂R¹¹, or —C(NH)N(H)C(O)N(H)R⁹; R³ is hydrogen, halo,alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹, —C(NH)NH₂,—C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, R¹²—C(O)N(R⁹)R¹⁰, —CH(OH)C(O)N(R⁹)R¹⁰,—N(R⁹)R¹⁰, —R¹²—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹²—C(O)OR⁹, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁵ and R⁶ areindependently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R⁹)R¹⁰,—C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰, —N(R⁹)C(O)N(R⁹)R¹⁰,—N(R⁹)C(O)R¹⁰, —N(R⁹)S(O)₂R¹¹, or —N(R⁹)C(O)N(R⁹)—CH₂C(O)N(R⁹)R¹⁰; R⁷ is—X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ or —X—C([C(R¹³)H]_(p)—C(R¹³)H₂)₂H where: pis 0 to 5; X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹)—; andeach R¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4),—[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —[CH₂]_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); orR⁷ is selected from the group consisting of the following formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —(CH₂)_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); andeach R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)— where: each r isindependently 0 to 5, and each X is —O—, —S(O)_(n)— (where n is 0 to 2),or —N(R⁹)—; and each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (wherem is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—(C(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen,alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); each R¹¹ is alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); and each R¹² is independently an alkylene oralkylidene chain; as a single stereoisomer or a mixture thereof; or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient.
 17. A method of treating a human having adisease-state characterized by thrombotic acitivity, which methodcomprises administering to a human in need thereof a therapeuticallyeffective amount of a compound selected from the groupo consisting ofthe following formulae:

wherein: A is —C(R⁸)═ or —N═ (where R⁸ is hydrogen, alkyl or halo); Z¹is —O—, —N(R⁹)—, —CH₂O— or —S(O)_(n)— (where n is 0 to 2); Z² is —O—,—N(R⁹)—, —OCH₂— or —S(O)_(n)— (where n is O to 2); R¹ and R⁴ are eachindependently hydrogen, halo, alkyl, nitro, —OR⁹, —C(O)OR⁹,—C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or —N(H)S(O)₂R¹¹; R² is—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹¹, —C(NH)N(H)C(O)R⁹,—C(NH)N(H)S(O)₂R¹¹, or —C(NH)N(H)C(O)N(H)R⁹; R³ is hydrogen, halo,alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹, —C(NH)NH₂,—C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹²—C(O)N(R⁹)R¹⁰, —CH(OH)C(O)N(R⁹)R¹⁰,—N(R⁹)R¹⁰, —R¹²—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹²—C(O)OR⁹, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁵ and R⁶ areindependently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R⁹)R¹⁰,—C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —C(O)N(R)CH₂C(O)N(R⁹)R¹⁰, —N(R⁹)C(O)N(R⁹)R¹⁰,—N(R⁹)C(O)R¹⁰, —N(R⁹)S(O)₂R¹¹, or —N(R⁹)C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰; R⁷ is—X—CH₂—[C(R¹³)H]_(p)—C(R¹³)H₂ or —X—C([C(R¹³)H]_(p)—C(R¹³)H₂)₂H where: pis 0 to 5; X is —O—, —S(O)_(n)— (where n is 0 to 2), or —N(R⁹); and eachR¹³ is independently —[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4),—[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —[CH₂]_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or—[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each n is independently 0 to 2); orR⁷ is selected from the group consisting of the following formulae:

where q is 0 to 4; p is 0 to 5; each R¹³ is independently—[C(OR⁹)H]_(m)—CH₂—OR⁹ (where m is 1 to 4), —[CH₂]_(n)—OR⁹,—[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰, —(CH₂)_(n)—OC(O)R⁹,—[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹, —[CH₂]_(n)—OC(O)OR¹¹,—[CH₂]_(n)—N(R⁹)C(O)OR¹¹, —[CH₂]_(n)—OC(O)N(R⁹)R¹⁰,—[CH₂]_(n)—N(R⁹)C(O)N(R⁹R¹⁰ (where each n is independently 0 to 2); andeach R¹⁴ is —X—[CH₂]_(r)— or —X—CH₂—[C(R¹³)H]_(r)—, where: each r isindependently 0 to 5, and each X is —O—, —S(O)_(n)— (where n is 0 to 2),or —N(R⁹)—; and each R¹³ is independently —[CH(OR⁹)]_(m)—CH₂—OR⁹ (wherem is 1 to 4), —[CH₂]_(n)—OR⁹, —[CH₂]_(n)—SR⁹, —[CH₂]_(n)—N(R⁹)R¹⁰,—[CH₂]_(n)—OC(O)R⁹, —[CH₂]_(n)—SC(O)R⁹, —[CH₂]_(n)—N(R⁹)C(O)R⁹,—[CH₂]_(n)—OC(O)OR¹¹, —[CH₂]_(n)—N(R⁹)C(O)OR¹¹,—[CH₂]_(n)—OC(O)N(R⁹)R¹⁰, or —[CH₂]_(n)—N(R⁹)C(O)N(R⁹)R¹⁰ (where each nis independently 0 to 2); each R⁹ and R¹⁰ is independently hydrogen,alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); each R¹¹ is alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); and each R¹² is independently an alkylene oralkylidene chain; as a single stereoisomer or a mixture thereof; or apharmaceutically acceptable salt thereof.